rs143141689

chr1-52397773-C-T

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 14P and 1B. PM1 PM2 PM5 PP5_Very_Strong BS1_Supporting

The NM_004153.4(ORC1):c.314G>A(p.Arg105Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000297 in 1,614,036 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R105W) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00031 (0 hom.)
• Consequence: ORC1 NM_004153.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 6.58

Genes affected

ORC1 (HGNC:8487): (origin recognition complex subunit 1) The origin recognition complex (ORC) is a highly conserved six subunits protein complex essential for the initiation of the DNA replication in eukaryotic cells. Studies in yeast demonstrated that ORC binds specifically to origins of replication and serves as a platform for the assembly of additional initiation factors such as Cdc6 and Mcm proteins. The protein encoded by this gene is the largest subunit of the ORC complex. While other ORC subunits are stable throughout the cell cycle, the levels of this protein vary during the cell cycle, which has been shown to be controlled by ubiquitin-mediated proteolysis after initiation of DNA replication. This protein is found to be selectively phosphorylated during mitosis. It is also reported to interact with MYST histone acetyltransferase 2 (MyST2/HBO1), a protein involved in control of transcription silencing. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jun 2010]

ACMG classification

Verdict is Pathogenic. Variant got 13 ACMG points.

• PM1: In a domain BAH (size 126) in uniprot entity ORC1_HUMAN there are 6 pathogenic changes around while only 2 benign (75%) in NM_004153.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-52397774-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 982308.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP5: Variant 1-52397773-C-T is Pathogenic according to our data. Variant chr1-52397773-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 30232.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.000312 (456/1461834) while in subpopulation NFE AF= 0.000375 (417/1111952). AF 95% confidence interval is 0.000344. There are 0 homozygotes in gnomad4_exome. There are 207 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ORC1	NM_004153.4	c.314G>A	p.Arg105Gln	missense_variant	4/17	ENST00000371568.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ORC1	ENST00000371568.8	c.314G>A	p.Arg105Gln	missense_variant	4/17	1	NM_004153.4	P1
ORC1	ENST00000371566.1	c.314G>A	p.Arg105Gln	missense_variant	4/17	1		P1

Frequencies

GnomAD3 genomes AF: 0.000158 AC: 24 AN: 152202 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000338

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000954 AC: 24 AN: 251480 Hom.: 0 AF XY: 0.0000662 AC XY: 9 AN XY: 135910

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000211

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000312 AC: 456 AN: 1461834 Hom.: 0 Cov.: 32 AF XY: 0.000285 AC XY: 207 AN XY: 727224

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000375

Gnomad4 OTH exome AF: 0.000596

GnomAD4 genome AF: 0.000158 AC: 24 AN: 152202 Hom.: 0 Cov.: 32 AF XY: 0.000121 AC XY: 9 AN XY: 74350

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000338

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000242 Hom.: 0

Bravo AF: 0.000159

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.0000824 AC: 10

EpiCase AF: 0.000164

EpiControl AF: 0.000237

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Meier-Gorlin syndrome 1 Pathogenic:3

Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 27, 2011	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Dec 30, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	The ORC1 c.314G>A (p.Arg105Gln) missense variant has been reported in two studies in which it is found in a total of seven individuals with Meier-Gorlin syndrome, including in one in a homozygous state and in six (including two siblings) in a compound heterozygous state with a truncating variant or splice acceptor site variant as the second allele (Bicknell et al. 2011; de Munnik et al. 2012). Control data are unavailable for this variant, which is reported at a frequency of 0.00047 in the European American population of the Exome Sequencing Project. Functional studies suggest that the p.Arg105Gln variant abolishes the ability of Orc1 to inhibit Cyclin E-CDK2 kinase activity (Hossain and Stillman 2012) and reduces DNA binding affinity leading to impaired nucleosome interaction (Zhang et al. 2015). Based on the evidence, the p.Arg105Gln variant is classified as pathogenic for Meier-Gorlin syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Sep 07, 2021	The sequence change, c.314G>A, in exon 4 results in an amino acid change, p.Arg105Gln. This sequence change has been previously described in the homozygous and compound heterozygous states in individuals and families with ORC1-related Meier-Gorlin syndrome (PMIDs: 21358632, 21358631, 22333897). This sequence change has been described in the gnomAD database with a low frequency of 0.023% in non-Finnish European subpopulation only (dbSNP rs143141689). The p.Arg105Gln change affects a highly conserved amino acid residue located in the BAH domain of the ORC1 protein. Functional studies indicates p.Arg105Gln disrupts the function of the ORC1 protein (PMID: 22855792, 25689043). Collectively this evidence suggests p.Arg105Gln is pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 19, 2022	Published functional studies demonstrate reduced ORC1 DNA binding affinity, leading to impaired ORC1-nucleosome reaction and a defect in regulation of centriole and centrosome copy numbers (Zhang et al., 2015; Hossain et al., 2012); This variant is associated with the following publications: (PMID: 22855792, 23516378, 30609409, 34426522, 14564153, 31980526, 26323792, 33477564, 11477602, 21358632, 23023959, 33761311, 21358633, 22333897, 21358631, 25689043) -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 19, 2023	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 105 of the ORC1 protein (p.Arg105Gln). This variant is present in population databases (rs143141689, gnomAD 0.02%). This missense change has been observed in individuals with Meier-Gorlin syndrome (PMID: 21358631, 21358632). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 30232). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt ORC1 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects ORC1 function (PMID: 22855792). For these reasons, this variant has been classified as Pathogenic. -

Meier-Gorlin syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Apr 13, 2016

The p.Arg105Gln variant in ORC1 has been reported in at least 5 individuals (1 h omozygous and 4 compound heterozygous with other disease-associated variants) wi th clinical features of Meier-Gorlin syndrome (Bicknell 2011, de Munnik 2012). T his variant has also been identified in 10/121,412 of chromosomes by the Exome A ggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs143141689). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. In vitro functi onal studies provide some evidence that the p.Arg105Gln variant may impact prote in function (Bicknell 2011, Hossain 2012, Zhang 2015). In summary, this variant meets our criteria to be classified as pathogenic for Meier-Gorlin syndrome in a n autosomal recessive manner based upon its co-occurrence with disease-causing v ariants in affected individuals, low frequency in control populations and functi onal evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Pathogenic	0.30
Cadd	Uncertain	25
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.31	T;T
Eigen	Pathogenic	0.73
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Uncertain	0.96	D
M_CAP	Uncertain	0.13	D
MetaRNN	Uncertain	0.71	D;D
MetaSVM	Uncertain	0.60	D
MutationAssessor	Uncertain	2.4	M;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-1.6	N;N
REVEL	Pathogenic	0.72
Sift	Benign	0.087	T;T
Sift4G	Benign	0.18	T;T
Polyphen		1.0	D;D
Vest4		0.57
MVP		0.92
MPC		0.67
ClinPred		0.46	T
GERP RS		5.2
Varity_R		0.32
gMVP		0.61

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs143141689; hg19: chr1-52863445;